Platinum complexes such as cisplatin and oxaliplatin are used in various cancerous regions as key drugs for multidrug therapy in cancer chemotherapy. However, it is known that the platinum complexes cause kidney disorders, nausea and vomiting, peripheral nerve disorders, bone marrow suppression, and the like as side effects, and this has been a problem for clinical use.
For the purpose of reducing these side effects and enhancing therapeutic effects, development of platinum complexes utilizing drug delivery technologies is in progress. Examples of DDS preparations of platinum complexes that have hitherto progressed to clinical trial stages may include, but not limited to, a coordination compound of platinum(II) diaminocyclohexane with a block copolymer (NC-4016) (see Patent Document 1), targeted liposomes (MBP-426) having oxaliplatin encapsulated therein (see Patent Document 2), a N,O-amidomalonate platinum diamine complex (AP5346) (see Patent Document 3), a coordination compound of cisplatin with a block copolymer (see Patent Document 4), and a liposome preparation of cisplatin (Lipoplatin) (see non-Patent Document 1). However, DDS preparations of platinum complexes that have come to be available in the market still do not exist.
In the above-mentioned DDS preparations of platinum complexes that have progressed to clinical trial stages, tetra-coordinated platinum complexes are used as the platinum complex; however, DDS preparations using hexa-coordinated platinum complexes have also been reported. Specific examples of a DDS preparation using a hexa-coordinated platinum complex may include a compound comprising gold nanorods as a carrier (see Non Patent Document 2), a compound obtained by conjugating a serine/threonine phosphatase-2A inhibitor between a carrier and a hexa-coordinated platinum complex (see Non Patent Document 3), a compound obtained by crosslinking a polymer as a carrier using a hexa-coordinated platinum complex (see Non Patent Document 4), a compound obtained by modifying micelles that include a hexa-coordinated platinum complex with folic acid (see Non Patent Document 5), a compound having a photoresponsive hexa-coordinated platinum complex conjugated to a carrier (see Non Patent Document 6), a compound capable of forming micelles by conjugating a hexa-coordinated platinum complex and daunomycin respectively to a polymer (see Non Patent Document 7), a compound capable of forming micelles by conjugating a hexa-coordinated platinum complex and paclitaxel respectively to a polymer (see Non Patent Document 8), and a compound having a cancer-targeting peptide conjugated to a hexa-coordinated platinum complex (see Non Patent Document 9).
An advantage of using a hexa-coordinated platinum complex may be that the hexa-coordinated platinum complex can be conjugated to a carrier of a DDS by a method different from that using a tetra-coordinated platinum complex, by utilizing the ligands at the axial positions. Furthermore, it is said that a hexa-coordinated platinum complex is generally less active compared to a tetra-coordinated platinum complex and is reduced to a tetra-coordinated complex by a substance having reducing activity in cells to thereby exhibit antitumor activity. Thus, it is expected that side effects will be reduced by using a hexa-coordinated complex (see Non Patent Document 10). Examples of a compound having reducing activity in cells may include glutathione and ascorbic acid, and it is known that the concentrations of those compounds in cells (including cancer cells) are higher than the concentrations of the compounds in blood. Thus, it is considered that a hexa-coordinated platinum complex is selectively converted to a highly active tetra-coordinated platinum complex in an reducing environment in cells. Meanwhile, although the values may vary depending on the Document, the intracellular concentration of ascorbic acid is 300 to 10,000 μM, and the concentration in blood is 30 to 51 μM (see Non Patent Documents 4 and 11). Releasability of a platinum complex from a carrier under the conditions with adding ascorbic acid has been demonstrated in Non Patent Documents 4 and 7.
In regard to the reducing property of low-molecular weight hexa-coordinated platinum complexes, it is known that the reducing property varies with the ligands at the axial positions. However, all of the hexa-coordinated platinum complexes used in Non Patent Documents 2 to 9 mentioned above are compounds in which any one or both of hydroxyl groups of a hexa-coordinated platinum complex which has two hydroxyl groups as ligands at the axial positions, are bonded to a carrier by ester bonding, and no further development has been progressed.